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Background: Non-specific interstitial pneumonia (NSIP) is an interstitial lung disease that can result in end-stage fibrosis. We investigated the influence of body composition and pulmonary fat attenuation volume (CTpfav) on overall survival (OS) in NSIP patients., Methods: In this retrospective single-center study, 71 NSIP patients with a median age of 65 years (interquartile range 21.5), 39 females (55%), who had a computed tomography from August 2009 to February 2018, were included, of whom 38 (54%) died during follow-up. Body composition analysis was performed using an open-source nnU-Net-based framework. Features were combined into: Sarcopenia (muscle/bone); Fat (total adipose tissue/bone); Myosteatosis (inter-/intra-muscular adipose tissue/total adipose tissue); Mediastinal (mediastinal adipose tissue/bone); and Pulmonary fat index (CTpfav/lung volume). Kaplan-Meier analysis with a log-rank test and multivariate Cox regression were used for survival analyses., Results: Patients with a higher (> median) Sarcopenia and lower (< median) Mediastinal Fat index had a significantly better survival probability (2-year survival rate: 83% versus 71% for high versus low Sarcopenia index, p = 0.023; 83% versus 72% for low versus high Mediastinal fat index, p = 0.006). In univariate analysis, individuals with a higher Pulmonary fat index exhibited significantly worse survival probability (2-year survival rate: 61% versus 94% for high versus low, p = 0.003). Additionally, it was an independent risk predictor for death (hazard ratio 2.37, 95% confidence interval 1.03-5.48, p = 0.043)., Conclusion: Fully automated body composition analysis offers interesting perspectives in patients with NSIP. Pulmonary fat index was an independent predictor of OS., Relevance Statement: The Pulmonary fat index is an independent predictor of OS in patients with NSIP and demonstrates the potential of fully automated, deep-learning-driven body composition analysis as a biomarker for prognosis estimation., Key Points: This is the first study assessing the potential of CT-based body composition analysis in patients with non-specific interstitial pneumonia (NSIP). A single-center analysis of 71 patients with board-certified diagnosis of NSIP is presented Indices related to muscle, mediastinal fat, and pulmonary fat attenuation volume were significantly associated with survival at univariate analysis. CT pulmonary fat attenuation volume, normalized by lung volume, resulted as an independent predictor for death., (© 2024. The Author(s).)

Background/aims: To compare the effects of abatacept and conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the progression and development of rheumatoid arthritis-associated interstitial lung disease (RA-ILD)., Methods: This multi-center retrospective study included RA patients receiving abatacept or csDMARDs who underwent at least two pulmonary function tests and/or chest high-resolution computed tomography (HRCT). We compared the following outcomes between the groups: progression of RA-ILD, development of new ILD in RA patients without ILD at baseline, 28-joint Disease Activity Score with the erythrocyte sedimentation rate (DAS28-ESR), and safety. Longitudinal changes were compared between the groups by using a generalized estimating equation., Results: The study included 123 patients who were treated with abatacept (n = 59) or csDMARDs (n = 64). Nineteen (32.2%) and 38 (59.4%) patients treated with abatacept and csDMARDs, respectively, presented with RA-ILD at baseline. Newly developed ILD occurred in one patient receiving triple csDMARDs for 32 months. Among patients with RA-ILD at baseline, ILD progressed in 21.1% of cases treated with abatacept and 34.2% of cases treated with csDMARDs during a median 21-month follow-up. Longitudinal changes in forced vital capacity and diffusing capacity for carbon monoxide were comparable between the two groups. However, the abatacept group showed a more significant decrease in DAS28-ESR and glucocorticoid doses than csDMARDs group during the follow-up. The safety of both regimens was comparable., Conclusion: Abatacept and csDMARDs showed comparable effects on the development and stabilization of RA-ILD. Nevertheless, compared to csDMARDs, abatacept demonstrated a significant improvement in disease activity and led to reduced glucocorticoid use.

Lung cancer and interstitial lung disease have similar risk factors and pathogenesis. The incidence of lung cancer associated with interstitial lung disease is increasing, and the problem of comorbidity has gradually attracted attention. Early diagnosis of lung cancer associated with interstitial lung disease is difficult, there are many factors influencing treatment, and the prognosis is poor. Interstitial lung disease affects the treatment options for lung cancer in comorbid patients, and lung cancer treatment will increase the risk of acute exacerbation of interstitial lung disease in comorbid patients. For patients with early-stage lung cancer complicated with interstitial lung disease who have surgical indications, the surgical method and extend of resection should be determined on the basis of MDT according to tumor stage and lung function. For patients with early-stage lung cancer combined with interstitial lung disease who are not suitable for surgery, the benefits and risks of complications of the radiotherapy should be weighed, and the appropriate radiotherapy regimen and dose should be selected. Chemotherapy is an effective treatment for patients with advanced lung cancer complicated with interstitial lung disease. Some chemotherapy regimens cause acute progression of interstitial lung disease, and the choice of chemotherapy regimen is particularly important. For lung cancer patients with interstitial lung disease who are positive for driver gene mutations, targeted drugs with low pulmonary toxicity should be selected. Patients with lung cancer combined with interstitial lung disease may benefit from immunotherapy, but the risk of immune-related pneumonia is increased. The occurrence of adverse reactions should be closely monitored during immunotherapy. In the future, more prospective clinical trials are needed to formulate reasonable and effective treatment regimens for lung cancer combined with interstitial lung disease to achieve a better prognosis.

Fibrosing interstitial lung diseases (ILDs) encompass a diverse range of scarring disorders that lead to progressive lung failure. Previous gene expression profiling studies focused on idiopathic pulmonary fibrosis (IPF) and bulk tissue samples. We employed digital spatial profiling to gain new insights into the spatial resolution of gene expression across distinct lung microenvironments (LMEs) in IPF, chronic hypersensitivity pneumonitis (CHP) and non-specific interstitial pneumonia (NSIP). We identified differentially expressed genes between LMEs within each condition, and across histologically similar regions between conditions. Uninvolved regions in IPF and CHP were distinct from normal controls, and displayed potential therapeutic targets. Hallmark LMEs of each condition retained distinct gene signatures, but these could not be reproduced in matched lung tissue samples. Based on these profiles and unsupervised clustering, we grouped previously unclassified ILD cases into NSIP or CHP. Overall, our work uniquely dissects gene expression profiles between LMEs within and across different types of fibrosing ILDs., (© 2024. The Author(s).)

Objective: Interstitial lung disease (ILD) is an important cause of mortality in patients with rheumatoid arthritis (RA). Early RA-ILD detection is essential to improve prognosis. Here, we investigated eight serological biomarkers that may contribute to RA-ILD detection., Method: Fifty-five patients from the Early Rheumatoid Arthritis Program were evaluated for ILD with high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) using the SCAPIS protocol. Blood samples were obtained for biomarker analysis, and patients' clinical records were reviewed. We defined ILD using five different models based on the measurements used to confirm ILD: Model A = HRCT; B = PFTs; C = A plus B; D = C plus symptoms; and E = D plus inhalations., Results: Among 55 patients, two had an ILD diagnosis before the study, but over one-third fulfilled the ILD criteria. Cancer antigen 15-3 (CA15-3) and matrix metalloproteinase-7 (MMP-7) differentiated between RA with and without ILD (all p < 0.05). Surfactant protein D (SP-D) showed similar trends, as did macrophage inflammatory protein-1β (MIP-1β) and chitinase 3-like protein-1 (YKL-40). Based on Pearson's correlation coefficients, MIP-1β and YKL-40 were significantly correlated with DAS28 (MIP-1β: 0.3; YKL-40: 0.4), ESR (MIP-1β: 0.3; YKL-40: 0.4), and CRP (only MIP-1β: 0.4) (all p < 0.05). CA15-3 was correlated with rheumatoid factor and anti-citrullinated peptide antibodies (Pearson's correlation 0.3; both p = 0.03)., Conclusions: CA15-3 was the most significant biomarker for ILD detection in RA patients with stable low disease activity, closely followed by MMP-7. SP-D, MIP-1β, and YKL-40 may also contribute to RA-ILD diagnosis.

Objectives: Early identification of interstitial lung disease (ILD) among patients with rheumatoid arthritis (RA) is a challenge for clinicians. The aim of this study was to evaluate screening algorithms for ILD by comparing the proportion of patients assigned a high-risk profile by three recently proposed models., Method: We used the four-factor risk score, categorizing patients into high and low risk; the ILD screening criteria, categorizing patients into high, intermediate, and low risk; and the risk score for detection of subclinical RA-ILD, with four different risk categories, on patients with RA followed for 5 years after the RA diagnosis with pulmonary function tests, dyspnoea score, and pulmonary imaging., Results: The four-factor risk score identified 22% of the cohort (25/115) as eligible for further ILD investigations, while the ILD screening criteria identified 37% as high risk (43/115) and 34% as intermediate risk (39/115). The risk score for detection of subclinical RA-ILD identified 44% of the cohort as being at increased risk, with 7% in the highest risk group. The agreement between high-risk groups in the two clinical ILD screening models was moderate (kappa 0.43). Three patients in the cohort had clinical or subclinical ILD, and they were identified as high risk in the two clinical models., Conclusion: The three algorithms identified approximately one-third of the cohort as being at increased risk of ILD. Further development and validation of these algorithms are needed to reduce false positives and balance the potential benefit of earlier ILD diagnosis and healthcare resources used for respiratory assessment.

Recent studies have demonstrated promising results of fibroblast activation protein (FAP) inhibitor (FAPI) PET in prognosticating and monitoring interstitial lung diseases (ILDs). As a first step toward successful translation, our primary aim was to validate the FAPI PET uptake through immunohistochemistry in patients with advanced ILD who underwent lung transplantation after a FAPI PET scan. Methods: This is a preliminary analysis of a single-center, open-label, single-arm, prospective exploratory biodistribution study of 68 Ga-FAPI-46 PET imaging in patients with ILD (NCT05365802). Patients with ILD confirmed by high-resolution CT and scheduled for lung transplant were included. Tissue samples of explanted lungs were obtained from both the central and peripheral lung parenchyma of each lobe. Additional samples were obtained from areas of the lung corresponding to regions of FAPI PET activity. Immunohistochemical staining was performed with an anti-FAP antibody. Percentages of FAP immunohistochemistry-positive area were measured semiautomatically using QuPath software. SUVs in the areas of pathologic samples were measured on FAPI PET/CT by referencing the gross photomap of the explanted lung. A Spearman correlation coefficient test was used to assess the relationship between FAPI PET uptake and FAP immunohistochemical expression in each specimen. Results: Four patients with advanced ILD who underwent FAPI PET/CT before lung transplantation were included. The types of ILD were idiopathic pulmonary fibrosis ( n = 2), rheumatoid arthritis-associated ILD ( n = 1), and nonspecific interstitial pneumonia ( n = 1). FAPI uptake was visualized mainly in the fibrotic area on CT. Twenty-nine surgical pathology samples from 3 patients were analyzed. FAP staining was predominantly positive in fibroblastic foci. FAPI PET SUV max and SUV mean showed a positive correlation with the immunohistochemical FAP expression score (SUV max : r = 0.57, P = 0.001; SUV mean : r = 0.54, P = 0.002). Conclusion: In this analysis conducted in patients who underwent lung transplantation after a FAPI PET scan, FAPI PET uptake was positively correlated with FAP immunohistochemistry. These findings provide a rationale for further investigation of FAPI PET as a potential imaging biomarker for ILD., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Lymphopenia is a unique manifestation of anti-MDA5 positive dermatomyositis with interstitial lung disease (MDA5 + DM-ILD). This study aimed to investigate the relationship between dynamic changes in peripheral lymphocytes and short-term prognosis in patients of MDA5 + DM-ILD. Two hundred sixty-three MDA5 + DM-ILD patients were divided into different groups according to lymphocyte count and death or survival within 1 month, then the differences in clinical features and outcomes were compared. Associations between lymphocytes and risk of death within 1 month were also investigated in different lymphocyte groups using Cox proportional hazard models. A generalized additive mixed model (GAMM) was established to analyze the dynamic changes of lymphocytes in the death 1-month group. Lymphocytes of the patients who died within 1 month were significantly lower than survivors by different lymphocyte grouping methods, and the total lymphocytes showed a gradually decreasing trend in non-survivors. And the difference between survivors and non-survivors was more obvious over time. The lowest tertile of baseline lymphocytes as a reference, the hazard ratios for death within 1 month in the highest tertile were 0.497 (95% CI 0.26-0.949, P for trend = 0.033) after adjustment for potential confounders. GAMM analysis found a mean daily decrease of lymphocytes (0.034 × 10^9/L) after admission in death 1-month patients. Low baseline lymphocytes and gradually declined lymphocytes are both associated with a high risk of death within 1 month. However dynamic changes in lymphocytes can better reflect the disease status and better predict the short-term prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. Key points •Low baseline lymphocytes and gradually decreased trend along time correlated with poor short-term prognosis in MDA5 + DM-ILD patients. •Dynamic changes of lymphocytes can better reflect the disease status and better predict the 1-month prognosis than baseline lymphocytes in MDA5 + DM-ILD patients. •Generalized additive mixed model (GAMM) analysis found that in 1-month non-survivors, peripheral blood lymphocytes decreased by 0.034 × 10^9/L per day, while the lymphocytes in survivors gradually increased., (© 2024. The Author(s).)

High-resolution computed tomography (HRCT) is important for diagnosing interstitial lung disease (ILD) in inflammatory rheumatic disease (IRD) patients. However, visual ILD assessment via HRCT often has high inter-reader variability. Artificial intelligence (AI)-based techniques for quantitative image analysis promise more accurate diagnostic and prognostic information. This study evaluated the reliability of artificial intelligence-based quantification of pulmonary HRCT (AIqpHRCT) in IRD-ILD patients and verified IRD-ILD quantification using AIqpHRCT in the clinical setting. Reproducibility of AIqpHRCT was verified for each typical HRCT pattern (ground-glass opacity [GGO], non-specific interstitial pneumonia [NSIP], usual interstitial pneumonia [UIP], granuloma). Additional, 50 HRCT datasets from 50 IRD-ILD patients using AIqpHRCT were analysed and correlated with clinical data and pulmonary lung function parameters. AIqpHRCT presented 100% agreement (coefficient of variation = 0.00%, intraclass correlation coefficient = 1.000) regarding the detection of the different HRCT pattern. Furthermore, AIqpHRCT data showed an increase of ILD from 10.7 ± 28.3% (median = 1.3%) in GGO to 18.9 ± 12.4% (median = 18.0%) in UIP pattern. The extent of fibrosis negatively correlated with FVC (ρ=-0.501), TLC (ρ=-0.622), and DLCO (ρ=-0.693) (p < 0.001). GGO measured by AIqpHRCT also significant negatively correlated with DLCO (ρ=-0.699), TLC (ρ=-0.580) and FVC (ρ=-0.423). For the first time, the study demonstrates that AIpqHRCT provides a highly reliable method for quantifying lung parenchymal changes in HRCT images of IRD-ILD patients. Further, the AIqpHRCT method revealed significant correlations between the extent of ILD and lung function parameters. This highlights the potential of AIpqHRCT in enhancing the accuracy of ILD diagnosis and prognosis in clinical settings, ultimately improving patient management and outcomes., (© 2024. The Author(s).)

Background: Neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease of unknown origin associated with hyperplasia of pulmonary neuroendocrine cells (PNECs). Diagnosis is based on the characteristic clinical picture and typical radiological imaging, and, in some cases, on lung biopsies. To date, no biochemical indicators of the disease have been identified., Aim: We aimed to determine biomarkers that could be useful in the management of children diagnosed with NEHI., Methods: Patients with NEHI and healthy children were enrolled. Concentrations of serum biomarkers secreted by PNECs (calcitonin gene-related peptide and gastrin-releasing peptide) and biomarkers of the destruction of alveolar capillary membrane (surfactant proteins A and D [SP-A and SP-D]; glycoprotein Krebs von den Lungen-6 [KL-6]; metalloproteinases 7 and 9 [MMP-7 and MMP-9]; tissue inhibitor of metalloprotease 1) were measured., Results: Fifty-two children with NEHI and 23 healthy children were included in the study. The median age of children with NEHI was 3.9 years. There were no differences in serum levels of biomarkers secreted by PNECs between groups. KL-6 levels were significantly higher in children with NEHI than in healthy ones (median 119.6 vs. 92.1 U/mL, p = 0.003); however, concentrations of KL-6 were low in both groups. No significant differences existed between groups for the remaining biomarkers associated with the destruction of the alveolar-capillary membrane., Conclusions: Measurement of serum biomarkers released by PNECs and those associated with the destruction of the alveolar-capillary membrane does not appear to be useful in the management of children with NEHI., (© 2024 Wiley Periodicals LLC.)

Objective: Lung computed tomography (CT) is a valid method for the detection and assessment of the progression of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. The objective of this study is to conduct a comparative analysis of the characteristics of individuals with RA-ILD, with and without radiographic progression, determined using lung CT scans., Method: In this retrospective observational study, three radiologists re-evaluated CT scans of RA-ILD patients who had at least one follow-up CT. The lungs were divided into upper, middle, and lower zones, with equal slices. Progression was defined as the involvement of more zones in the vertical extent by the same elementary findings or the emergence of more severe findings in the same zones compared to the previous examination. Logistic regression analysis was used to assess the possible factors identified in univariate analysis., Results: This study included 104 patients with 215 lung CT scans for analysis. Radiographic progression was seen in 43 patients (41.3%). Male sex, findings compatible with ILD on the last X-ray, age at diagnosis of ILD > 50 years, and presence of ground-glass opacity on CT were more common in the group with progression. In multivariate analysis (adjusted for ILD disease duration), findings consistent with ILD on chest X-ray and male sex were independent risk factors for progression, while taking methotrexate (ever) was an independent protective factor for progression., Conclusion: Our findings indicate a negative association between methotrexate use and ILD progression. These results should be confirmed in further studies.

Background: Anti-fibrotics can reduce restrictive impairment in idiopathic pulmonary fibrosis (IPF). However, its effectiveness in non-IPF progressive fibrosing interstitial lung disease (non-IPF PF-ILD) remains uncertain., Objective: We assess the efficacy and safety of anti-fibrotics pirfenidone and nintedanib versus placebo among non-IPF PF-ILD adult patients., Methods: Meta-analysis was performed using PubMed, SCOPUS, and Cochrane databases to identify randomized controlled trials (RCTs). At respective centers, non-IPF PF-ILD was defined as clinical and radiological findings inconsistent with IPF and greater than 5 % forced vital capacity (FVC) decline, worsening radiological fibrosis or respiratory symptoms., Results: Among seven RCTs involving 1,816 non-IPF PF-ILD patients, anti-fibrotics significantly reduced decline in FVC from baseline in milliliters (MD -66.80milliliters; P < 0.01) and percent predicted (MD -1.80 %; P < 0.01) compared to placebo. However, severity of FVC decline was less than 10 % (P = 0.33) in both groups. No significant difference in the decline of 6MWD from baseline in meters (P = 0.19) while on anti-fibrotics, although those on pirfenidone had less decline in 6MWD (MD -25.12 m; P < 0.01) versus placebo. The rates of all-cause mortality (P = 0.34), all-cause hospitalization (P = 0.44), and hospitalization for respiratory etiology (P = 0.06) were comparable in both groups. Adverse events of nausea/vomiting (54.2 % vs. 20.3 %; P < 0.01), diarrhea (65.2 % vs. 27.6 %; P = 0.02), anorexia/weight loss (23.0 % vs. 7.7 %; P < 0.01), neurological disorders (20.8 % vs. 12.6 %; P < 0.01), and events requiring therapy discontinuation were higher (18.4 % vs. 9.9 %; P < 0.01) in the anti-fibrotic group. Other adverse events of skin (P = 0.18) and respiratory disorders (P = 0.20) were equal., Conclusion: The advent of anti-fibrotics offers alternative treatment to reduce lung function decline., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: To date there are no data on sex aspects evaluating outcomes of interventional pneumology (IP). Our aim was to investigate sex differences in transbronchial lung cryobiopsy (TBLC) outcomes in the diagnosis of interstitial lung disease (ILD)., Methods: All consecutive (TBLC)s performed for ILD evaluation between Nov 17 and Dec 21 at a tertiary referral center for ILDs and IP were analyzed. The indication for the procedure was determined by a multidisciplinary discussion (MDD). Final results including bronchoalveolar lavage (BAL) and histology were discussed in a 2nd MDD and outcomes and procedure related complications were assessed., Results: TBLC was performed in 406 patients (38.4 % female/67.8 years/FVC 76.8 %). Among 32 interventionalists, 16 females performed 53 % of interventions. Females had longer procedure times (29.9 vs. 26.6 min, p = 0.046), used fluoroscopy more often (76.7 vs. 50.3 %, p < 0.001) and obtained more samples (3.6 vs. 3.2, p = 0.021) than their male counterparts. No difference was found for major bleeding or pneumothorax. MDD was able to conclude on a diagnosis in 88.4 % of interventions performed by women and in 78.5 % performed by men (p = 0.010). In a multivariate analysis, female gender (OR 1.93) and lower FVC% values (OR 0.98) were significantly associated with diagnostic yield, whereas the number of biopsies, professional experience, use of fluoroscopy or antiplatelet drugs were not relevant., Conclusion: The results of this study strengthen the role of women in endoscopy and may help to motivate women to pursue a career in IP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: FCT received research funding from Octapharma Pharmazeutika Produktionsgeselltschaft m.b.H. to conduct this study; the funder had no influence on the evaluation and interpretation of the data. FCT has received honoraria for lectures from Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Grifols, Novartis, CSL Behring. She participates in an Advisory Board for CSL Behring, GlaxoSmithKline and Boehringer Ingelheim, outside the submitted work. RE reports honoraria or payment for lectures and presentations from Broncus, Olympus, Pentax, Pulmonx, Astra Zeneca. He joins the data safety monitoring board for Intuitive Surgical Inc, outside the submitted work. FJFH reports Research Support from Olympus Medical, Pulmonx, Broncus, Uptake Medical, Roche Diagnostics, BMBF, DFG, EU, Klaus-Tschira Stiftung, BMG; Lecturing honoraria from Pulmonx, Uptake Medical, Roche Diagnostics, Astra Zeneca, Boehringer Ingelheim, Novartis, Berlin Chemie, Chiesi, Medupdate, Erbe, GSK and consulting activities for Olympus Medical, Pulmonx, Broncus – Uptake Medical, Roche Diagnostics, Astra Zeneca, J&J, Karger, LÄK, Boston Scientific, Dinova, Nanovation, Free Flow Medical, Erbe, outside the submitted work. KKo. Has received honoraria for lectures from Berlin-Chemie, Astra Zeneca and Boston Scientific, outside the submitted work. KKa has received honoraria for lectures form Berlin-Chemie, Astra Zeneca, Boehringer Ingelheim, Insmed, outside the submitted work. JDM, CA, MS, ME, MP, MK have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A 70-year-old woman with anti-aminoacyl-tRNA synthetase (ARS) antibody-positive interstitial lung disease (ARS-ILD) received daily medications and regular cyclophosphamide cycles for recurring exacerbations. Approximately four years after immunosuppression initiation, the patient was admitted for progressive dyspnea on exertion. Chest computed tomography (CT) findings were suggestive of acute exacerbation. Despite intensified immunosuppressive treatment, the radiographic findings worsened, and serum Krebs von den Lungen-6 (KL-6) levels increased. A bronchoalveolar lavage fluid (BALF) examination revealed amorphous globules and alveolar macrophages with eosinophilic granules. Owing to negative anti-granulocyte-macrophage colony-stimulating factor antibody tests, a diagnosis of secondary pulmonary alveolar proteinosis (PAP) was established.

Objectives: To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups., Methods: Participants with sera, high-resolution CT and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. Twenty-seven of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc., Results: A total of 407 participants were identified, 252 (61.9%) with SSc-ILD. The median (interquartile range) follow-up after biomarker measurement was 6.31 (3.11-9.22) years. Sixteen biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality [hazard ratio (HR) 3.55; 95% CI 2.37-5.33; P < 0.001]. Five additional biomarkers had an HR >2: SP-D (2.28, 1.57-3.31; P < 0.001), E-selectin (2.19, 1.53-3.14; P < 0.001), IL-6 (2.15, 1.50-3.09; P < 0.001), MMP-3 (2.05, 1.42-2.95; P < 0.001) and ET-1 (2.03, 1.40-2.92; P < 0.001). Eleven biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at 1-year follow-up: CXCL4 (odds ratio 2.67, 1.46-4.88; P = 0.001), MMP-1 (2.56, 1.43-4.59; P = 0.002) and ET-1 (2.18, 1.24-3.83; P = 0.007)., Conclusion: Multiple biomarkers, especially VCAM-1, E-selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Many patients with chronic obstructive pulmonary disease and fibrotic interstitial lung disease suffer from severe dyspnea and reduced quality of life, despite receiving optimal disease-modifying treatment for their illness. Studies have suggested that these patients may benefit from treatment with low-dose opioids. However, many patients decline opioid treatment. This has led to patients not receiving proper palliative treatment of their lung disease., Aim: To identify potential barriers that prevent patients from receiving adequate palliative care with opioids and enable doctors to address patients' concerns., Design: A qualitative study based on semi-structured interviews. Interviews were transcribed and thematic analysis was done using NVivo., Setting/participants: Patients were recruited when scheduled for out-patient follow-up at Center for Rare Lung Diseases or at the COPD clinic, Aarhus University Hospital. Eligible patients were 18 years of age, did not currently receive opioids or had ever received opioids for dyspnea., Results: A total of 28 patients participated. One patient was excluded before final analysis of 27 patients. Four themes were identified: Fear of side-effects, Need for more information, Stigma of opioids association with severe illness and dying, and No discernible barriers. Furthermore, three sub-themes to Fear of side-effects were identified: Fear of addiction, concern for sedative effect, and fear for loss of mobility due to inability to drive a car. The most expressed concern was Fear of side-effects, especially addiction., Conclusions: Pre-conceived notions about opioids prevent some patients with chronic obstructive lung disease or interstitial lung disease from receiving palliative care for breathlessness., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aim: Pepsin is an enzyme that helps digest protein secreted only from the gastric chief cell in an inactive state. Pepsin is a good marker for acidic gastroesophageal reflux (GER). Its presence in sputum or saliva is considered pathologic. In GER, cough is stimulated by broncho-esophageal neurogenic reflex and aspiration of gastric contents into the airways. GER is the most common cause of cough. Gastric acid reflux is also thought to play a role in Interstitial Lung Disease (ILD) etiology. In many studies, pepsin and bile acid levels in bronchial lavage were high in patients with interstitial lung disease and chronic cough. In our study, we aimed to evaluate pepsin levels in bronchial lavage in patients with ILD and chronic cough and to investigate the relationship between symptoms and reflux treatment., Methods: Between January 2021 and February 2022, 212 patients who underwent bronchoscopy in our tertiary clinic were evaluated. These patients were divided into three groups: 52 patients with interstitial lung disease, 81 patients with chronic cough, and 79 patients who underwent bronchoscopy with a pre-diagnosis of lung cancer as the control group. Bronchial lavage obtained by bronchoscopy was analyzed for pepsin levels., Results: Shortness of breath and cough were the most common symptoms in all three groups. Pepsin levels were 16.71 ± 8.6 ng/ml in the chronic cough group, 15.6 ± 8.9 ng/ml in the ILD group, and 10.58 ± 5.4 ng/ml in the lung cancer (control) group. Pepsin levels in the ILD and chronic cough group were statistically significantly higher than in the lung cancer group (p:0.00). There was no statistical difference between the ILD group and the chronic cough group regarding pepsin levels. It was found that pepsin levels were lower in the three groups who received anti-reflux treatment. There was no difference in pepsin levels between ILD subgroups., Conclusion: Pepsin levels in bronchial lavage were higher in the ILD and chronic cough groups. This suggests that reflux may be involved in the etiology of chronic cough and ILD. Low pepsin values in patients receiving anti-reflux therapy have shown that occult reflux may occur. In our study, the high level of pepsin in bronchial lavage, especially in the chronic cough and ILD group, may be instructive in the etiology and treatment planning of the disease., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The impact of autoantibody profiles on the prognosis for idiopathic inflammatory myositis-associated interstitial lung disease (IIM-ILD) and myositis spectrum ILD with myositis-specific antibodies (MSAs) remains unclear. This retrospective cohort study examined whether serological profiles were associated with mortality or longitudinal lung function change., Methods: The baseline clinical/demographic characteristics and follow-up lung function data of consecutive adult patients with IIM-ILD or interstitial pneumonia with autoimmune features (IPAF) positive for MSAs (IPAF-MSA) were extracted from three hospitals. Univariate and multivariate Cox proportional hazards analyses were used to compare mortality between groups of patients with different autoantibodies. Regression models were used to analyse their lung function trends., Results: Of the 430 included patients, 81% met the IIM criteria, and the remaining 19% were diagnosed with IPAF-MSA. On univariate analysis, the risk factors associated with mortality included higher age, Charlson Comorbidity Index, and CRP; and lower BMI, baseline TLCO% and FEV1%. Compared with anti-MDA5 negativity, anti-MDA5 positivity (MDA5+) was associated with higher mortality in the first 3 months [hazard ratio (HR) 65.2, 95% CI 14.1, 302.0], while no significant difference was seen thereafter (HR 0.55, 95% CI 0.14, 2.28). On multivariate analysis, combined anti-synthetase antibodies were associated with a reduced risk of mortality (HR 0.63), although individually, mortality was reduced in patients with anti-Jo1+ (HR 0.61, 95% CI 0.4-0.87) and increased in patients with anti-PL7+ (HR 2.07, 95% CI 1.44-2.99). Anti-MDA5+ was associated with slow improvement in %FVC over the first 3 years, while anti-PL7+ was linked with a slow decline from 12 months onwards., Conclusion: Among the autoantibody profiles in myositis spectrum disorders, anti-MDA5+ and anti-PL7+ conferred higher mortality risks in patients with IIM-ILD. Survivors of an early peak of mortality in anti-MDA5+ disease appeared to have a favourable prognosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: The Chester Step Test (CST) is a simple and inexpensive field test, which requires minimal physical space to assess exercise capacity. Such characteristics make the CST suitable to be used in different settings, however, its measurement properties in patients with interstitial lung diseases (ILD) are unknown., Methods: A cross-sectional study was conducted in patients with ILD. First, a CST-1 and a 6-minute walk test (6MWT) were performed. After 48-72 hours, a CST-2 was repeated. A 2nd rater was present in one of the sessions. Relative reliability was measured using intraclass correlation coefficient (ICC 1,1 and ICC 2,1 ). Absolute reliability was determined using standard error of measurement (SEM), minimal detectable change at 95% confidence interval (MDC 95 ) and the Bland-Altman method. The values of SEM and MDC 95 were also expressed as a percentage of the mean. Construct validity was explored using Spearman correlation coefficient (r s ) between the number of steps taken in the best CST and the distance performed in the 6MWT., Results: Sixty-six patients with ILD (65.5±12.9 years; 48.5%men; FVC 79.4±18.8pp; DL CO 49.0±18.3pp) participated in the study. Relative (ICC 0.95-1.0) and absolute reliability were excellent without evidence of systematic bias. The SEM and MDC 95 were 11.8 (14.7%) and 32.6 steps (40.7%), respectively. The correlation between CST and 6MWT was significant, positive, and high (r s =0.85, p=0.001)., Conclusion: The CST is a reliable and valid test and might be especially useful to assess exercise capacity in patients with ILD in limited space environments., Competing Interests: Conflicts of interest The authors report no financial, or non-financial, conflicts of interest in this work., (Copyright © 2022 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Sjögren's syndrome (SS) can present with extraglandular organs, such as interstitial lung disease (ILD). Anti-SS-A antibody is frequently found in SS cases, whereas anti-centromere antibody (ACA) is detected in some SS cases. Notably, the anti-SS-A and ACA double-positive cases exhibited distinct features with a higher prevalence of ILD. However, there have so far been no reports on the treatment of ILD in anti-SS-A and ACA double-positive cases. We herein present a case of ILD with anti-SS-A and ACA double-positive SS that was successfully treated with immunosuppressive therapy. Our case suggests the potential efficacy of immunosuppressive therapy for this poorly understood condition.

Objectives: Lung ultrasound (LUS) and high-resolution CT (HRCT) are commonly used for the evaluation of interstitial lung disease (ILD). Nintedanib (NIN) is an antifibrotic therapy approved for systemic sclerosis-associated ILD (SSc-ILD). We assessed LUS and quantitative HRCT changes in SSc-ILD patients treated with NIN during a 1 year follow-up, evaluating relationships between imaging variations and functional or quality-of-life outcomes., Methods: SSc-ILD patients who started NIN were enrolled and followed for 12 months. Pulmonary function tests and patient-reported outcome measures (PROMs) were assessed half-yearly and quarterly, respectively. LUS was performed quarterly evaluating the presence of B-lines (BL) and pleural line irregularities (PLI). HRCT was repeated after 1 year and quantitatively analysed with CALIPER software., Results: Ten patients (70% female, mean age 62 years) were enrolled. The mean total number of both BL and PLI was constantly decreased during NIN treatment, being significantly reduced after 12 months (from 175.1 [66.7] to 120.8 [70.3] for BL, P = 0.005; and from 50.6 [32.5] to 37.2 [22.4] for PLI, P = 0.05). Male gender, smoking habit and baseline forced vital capacity <70% predicted were associated with worse LUS outcomes. A greater reduction in both BL and PLI was observed in those who improved in PROMs, especially modified Medical Research Council dyspnoea scale (P = 0.016 and P = 0.04, respectively) and Saint George's Respiratory Questionnaire (P = 0.006 and P = 0.026, respectively). No significant changes in the CALIPER percentages of normal parenchyma or ILD elements were observed after 12 months of NIN, thus paralleling the stabilization obtained at pulmonary function tests., Conclusion: We present preliminary results on NIN effects on SSc-ILD as assessed by LUS, a useful method for frequently repeated monitoring, and CALIPER, a valid implementation whenever a HRCT is performed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pulmonary hypertension (PH) associated with chronic lung disease (CLD) is both common and underrecognised. The presence of PH in the setting of lung disease has been consistently shown to be associated with worse outcomes. Recent epidemiological studies have advanced understanding of the heterogeneity of this patient population and shown that defining both the specific type of CLD as well as the severity of PH ( i.e. deeper phenotyping) is necessary to inform natural history and prognosis. A systematic diagnostic approach to screening and confirmation of suspected PH in CLD is recommended. Numerous uncontrolled studies and one phase 3 randomised, controlled trial have suggested a benefit in treating PH in some patients with CLD, specifically those with fibrotic interstitial lung disease (ILD). However, other studies in diseases such as COPD-PH showed adverse outcomes with some therapies. Given the expanding list of approved pharmacological treatments for pulmonary arterial hypertension, developing a treatment algorithm for specific phenotypes of CLD-PH is required. This article will summarise existing data in COPD, ILD and other chronic lung diseases, and provide recommendations for classification of CLD-PH and approach to the diagnosis and management of these challenging patients., Competing Interests: Conflict of interest: O.A. Shlobin reports consultancy fees from United Therapeutics, Merck, Janssen and Aerami, payment or honoraria for lectures, presentations, manuscript writing or educational events from Ferrera and United Therapeutics, participation on a data safety monitoring board or advisory board with Janssen, and leadership roles with ACCP/Chest and World Symposium on Pulmonary Hypertension task force. Y. Adir reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD Israel and Bayer Israel, support for attending meetings from BI Israel and RAFA Israel, and participation on a data safety monitoring board or advisory board with MSD, GB and Acceleron. J.A. Barbera reports grants from Merck Sharp & Dome and Ferrer International, consultancy fees from Merck Sharp & Dome, Janssen-Cilag and Ferrer International, payment or honoraria for lectures, presentations, manuscript writing or educational events from Merck Sharp & Dome, Janssen-Cilag, Ferrer International and AOP Orphan, support for attending meetings from Merck Sharp & Dome and Janssen-Cilag, and a leadership role with the World Symposium on Pulmonary Hypertension task force. V. Cottin reports consultancy fees and payment or honoraria for lectures, presentations, or educational events from Ferrer/United Therapeutics. S. Harari reports consultancy fees from Roche-Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, participation on a data safety monitoring board or advisory board “Prise en charge pragmatique de la fibrose pulmonaire idiopathique en progression: essai randomisé PROGRESSION-IPF”, and leadership roles with the World Symposium on Pulmonary Hypertension task force, FERS of the ERS and officer of the society, and FATS of the ATS. E-M. Jutant reports consultancy fees from Chiesi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, GSK, MSD and AstraZeneca, support for attending meetings from Janssen and MSD, and a leadership role with the World Symposium on Pulmonary Hypertension task force. J. Pepke-Zaba reports grants from MSD, consultancy fees from MSD, Janssen, Gossamer and Ferrer, support for attending meetings from Janssen, and a leadership role with the World Symposium on Pulmonary Hypertension task force. H-A. Ghofrani reports consultancy fees from Gossamer Bio, Inc., Aerovate, Altavant, Bayer AG, Attgeno, Janssen/Actelion, MSD/Acceleron, Pfizer, Liquidia, Morphic and Keros, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer AG, Janssen/Actelion, Gossamer Bio, Keros and MSD/Acceleron, participation on a data safety monitoring board or advisory board with Aerovate, Altavant, Attgeno, Janssen/Actelion, Insmed, MSD/Acceleron, Pfizer and Bayer AG, and the following financial (or non-financial) interests: the author's spouse is and employee of Liquidia. R. Channick reports consultancy fees from Bayer, Merck, Gossamer, Respira and Janssen, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer and Janssen, and participation on a data safety monitoring board or advisory board with Altavant., (Copyright ©The authors 2024.)

This study investigated the relationships between dietary sodium intake and the incidence and prevalence of interstitial lung disease (ILD) and pulmonary sarcoidosis using data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. This study assessed the strength of the abovementioned relationships via LASSO analysis and a generalized additive model with Poisson regression and determined the nonlinear and lagged effects via a distributed lag nonlinear model (DLNM). In the past three decades, global dietary sodium intake has decreased gradually. Two LASSO and generalized additive analyses both suggested that dietary sodium intake is obviously correlated with the incidence and prevalence of ILD and pulmonary sarcoidosis. The overall exposure‒response curve revealed a dose‒effect relationship between dietary sodium intake and the incidence and prevalence of ILD and pulmonary sarcoidosis. The maximum lag-specific RR of extremely high dietary sodium intake was 1.75 (95% CI: 1.61-1.91, lag 0 year) for incidence and 3.19 (95% CI: 2.24-4.53, lag 0 year) for prevalence relative to the reference. Our study suggests that dietary sodium intake is positively associated with the incidence and prevalence of ILD and pulmonary sarcoidosis. These findings may have important policy implications for dietary sodium intake-reduction strategies to decrease the burden of respiratory diseases and promote public health., (© 2024. The Author(s).)

Background: Transbronchial lung cryobiopsy (TBLC) has emerged as a promising diagnostic tool for interstitial lung disease (ILD). This study aimed to assess the initial experience, procedural learning curve, and influence of sedative medications on complication rates, particularly bleeding and pneumothorax, in the implementation of a TBLC program for ILD diagnosis., Methods: In this retrospective cohort study, we analysed 119 patients who underwent TBLC at Nippon Medical School Hospital from April 2021 to March 2024. Procedural times, complication rates, and histopathological outcomes were evaluated. The learning curve was assessed using cumulative sum (CUSUM) analysis, focusing on procedure time and biopsy yield. The association between sedative medication dosages and bleeding risk was also examined., Results: The overall diagnostic yield was high, with alveolar tissue obtained in 97.5% of cases and a definitive pathological diagnosis achieved in 81.5% of patients. CUSUM analysis revealed a proficiency threshold at approximately 56 cases, with improved efficiency and biopsy yield in the consolidation phase. Fentanyl dosage was significantly associated with reduced bleeding complications (odds ratio 0.51, 95% confidence interval 0.27-0.97, p = 0.041)., Conclusions: TBLC is a safe and effective diagnostic tool for ILDs, with a manageable learning curve for procedural efficiency. Sedation, particularly fentanyl dosage, may plays a crucial role in minimizing complications, but further research is needed to clarify this relationship. These findings support the adoption of TBLC as a standard diagnostic approach for ILD and highlight the importance of adequate training and optimized sedation protocols to ensure safety and efficacy in clinical practice., (© 2024. The Author(s).)

Backgroud: Anti-melanoma differentiation-associated protein 5 antibody-positive dermatomyositis (anti-MDA5-positvie DM) is a subtype of dermatomyositis with a poor prognosis, characterized by rapidly progressive interstitial lung disease (RP-ILD). The study aims to investigate the significance of serum cytokines profiles and peripheral lymphocytes in predicting prognoses of anti-MDA5-positvie DM with RP-ILD. Furthermore, it seeks to analyze longitudinal data of lymphocytes during hospitalization to identify distinct trajectories and cluster patients accordingly., Methods: A total of 168 patients with anti-MDA5-positive DM were enrolled in this retrospective study from two cohorts. Univariate and multivariate Cox regression analyses were conducted to determine the predictors of 6-month all-cause mortality and RP-ILD. Group-based trajectory modeling (GBTM) was employed to model the trajectories of longitudinal peripheral lymphocytes., Results: In the multivariate Cox regression analysis, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 10 9 /L, lymphocytes from 0.5 to 1.0 × 10 9 /L, older age, and elevated LDH were identified as independent predictors of 6-month all-cause mortality. Furthermore, IL-6 ≥ 13.41pg/mL, lymphocytes < 0.5 × 10 9 /L, and lymphocytes from 0.5 to 1.0 × 10 9 /L were found to be independent predictors of RP-ILD. Additionally, three trajectory groups of lymphocytes within the first week after admission were established based on GBTM. These groups included: Group 1, with low-level of lymphocytes that declined; Group 2, with medium-level of lymphocytes that slightly rose; and Group 3, with high-level of lymphocytes that rose. Notably, group 1 showed the highest mortality (90.7%) and all experiencing RP-ILD. Increased expression of IL-6 in lung tissues was observed in two cases with RP-ILD compared to two cases without RP-ILD. We also found the increased infiltration of CD4 + and CD8 + T cells, particularly CD8 + T cells, in lung tissues from patients with RP-ILD., Conclusions: Our study demonstrated that increased level of serum IL-6 (≥ 13.41pg/mL) and severe lymphopenia were promising predictors of 6-month all-cause mortality and the occurrence of RP-ILD in anti-MDA5-positive DM patients. Furthermore, tracking distinct trajectories of lymphocytes during hospitalization can be utilized to cluster patients., (© 2024. The Author(s).)

Idiopathic inflammatory myopathy (IIM) with autoantibodies recognizing the signal recognition particle (SRP) is characterized by prominent proximal weakness, infrequent extramuscular involvement, dramatically elevated creatine kinase levels, and myofiber necrosis with few inflammatory cell infiltrates in muscle tissue. To enhance understanding of the clinically used diagnosis and treatment of this disease, this study presents a single-center experience and analysis of a Chinese cohort with anti-SRP IIM. The most recent European Neuromuscular Center criteria were used to include Anti-SRP IIM patients from September 2016 to November 2019. Prior to treatment initiation, all sera were collected for the detection of anti-SRP autoantibodies and other myositis-related autoantibodies. Muscle strength, concurrent autoimmune conditions, comorbidities like interstitial lung disease (ILD), treatment outcomes, and follow-up results were also documented. Univariate logistic regression was employed to determine factors affecting prognosis. Among 271 patients with IIM, we identified 23 (8.5%) patients with anti-SRP IIM. Lower limb muscle weakness was frequently more severe. Interstitial lung disease (ILD) was observed in 50% of anti-SRP IIM patients. The presence of ILD may serve as a predictor of a poor prognosis, as revealed by univariate logistic regression analysis (odds ratio, 3.8, 95% CI: 1.0-6.8, p = 0.05).This Chinese Anti-SRP IIM cohort from Hunan province seems to have higher incidences of ILD, and associated ILD may be a risk factor for a poor prognosis. To fully understand the specific role of the anti-SRP autoantibody in this unique subset with ILD, further research is necessary., (© 2024. The Author(s).)

Background: Systemic sclerosis-related interstitial lung disease (SSc-ILD) represents a significant cause of morbidity and mortality in Systemic Sclerosis (SSc). Mycophenolate mofetil (MMF) is currently the first line treatment for SSc-ILD. There is no recommendation on the dosage of mycophenolic acid (MPA) blood concentrations, so we aimed to study the correlation between MPA exposure and respiratory outcomes in this population., Methods: We conducted a retrospective cohort study of SSc-ILD patients treated with MMF in our center. According to our policy, a complete patient evaluation was performed approximately one year after MMF initiation, during which the mycophenolic acid (MPA) residual rate (RR) was measured. We analyzed the association between RR and changes in forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) over time., Results: Forty-three SSc-ILD patients were included. Patients with higher RR levels (≥ 1.5 mg/L) had a significantly better FVC evolution with a higher proportion of stabilization and lower proportion of FVC decrease (p = 0.024). RR above 1.5 mg/L was a predictive factor of reduced FVC decline compared with lower RR levels adjusting for MMF dose and duration of MMF exposure (p = 0.008). There was no difference regarding DLCO outcome., Conclusion: Our study suggests that optimal MPA exposure, as indicated by RR levels, may better protect against FVC decline in SSc-ILD patients treated with MMF. Routine monitoring of MPA exposure could be beneficial in optimizing treatment outcomes. Prospective, multicenter studies are needed to further explore the relationship between MPA exposure and clinical outcomes in SSc-ILD., (© 2024. The Author(s).)

Background: Interstitial lung disease (ILD) is a serious complication in systemic juvenile idiopathic arthritis (SJIA). This study aimed to identify the clinical characteristics and prognosis of SJIA-ILD., Methods: A two-center retrospective cohort study was conducted on patients newly diagnosed with SJIA in China from October 2010 to December 2021. Clinical characteristics, laboratory parameters, outcomes, and relapse rates were compared between ILD and non-ILD groups., Results: A total of 176 children with SJIA were included, including 35 in ILD group and 141 in non-ILD group. The median age at onset of SJIA was 5.8 years (range 4.4-9.5) in patients with SJIA-ILD. It exhibited higher incidences of cervical spine (28.6%) and hip involvement (40.0%) in ILD group (P = 0.031 and P = 0.029, respectively). The incidence of macrophage activation syndrome (MAS) in ILD group reached up to 40%, significantly elevated than that in non-ILD group (P = 0.047). Children with ILD demonstrated a stronger inflammatory response and were more prone to developing lymphopenia (P = 0.009), requiring more combination therapy (P = 0.006) to control disease activity. 54.3% of patients received biologic therapies, with only three patient receiving biologics (one with IL-6 blockade, two with TNF inhibitor) prior to ILD onset and none receiving IL-1 blockade. The median follow-up duration was 6.0 years (range 3.9-9.5). The proportions of patients with SJIA-ILD achieving clinical inactive disease without glucocorticoids within 6 to 12 months of the treatment were significantly lower than control group (45.7% vs. 70.2%, P = 0.006). In ILD group, only 54.3% of patients achieved complete remission, and 17.1% were in a non-remission state, among whom two deaths from respiratory failure. There was no significant difference in disease relapse rates between the two groups (P > 0.05)., Conclusions: Patients with SJIA-ILD exhibited heightened inflammation, increased hip joint and cervical spine involvement, and were more susceptible to developing lymphopenia and MAS, suggesting a relatively poor prognosis. They required a prolonged time to control inflammation and more aggressive treatment strategies to achieve inactive status. The unsatisfactory rate of complete remission highlighted an urgent need for focused clinical strategies., (© 2024. The Author(s).)

Background: The quantitative analysis of computed tomography (CT) and Krebs von den Lungen-6 (KL-6) serum level has gained importance in the diagnosis, monitoring, and prognostication of interstitial lung disease (ILD). However, the associations between quantitative analysis of CT and serum KL-6 level remain poorly understood., Methods: In this retrospective observational study conducted at tertiary hospital between June 2020 and March 2022, quantitative analysis of CT was performed using the deep learning-based method including reticulation, ground glass opacity (GGO), honeycombing, and consolidation. We investigated the associations between CT-based phenotypes and serum KL-6 measured within three months of the CT scan. Furthermore, we evaluated the performance of the combined CT-based phenotypes and KL-6 levels in predicting hospitalizations due to respiratory reasons of ILD patients., Results: A total of 131 ILD patients (104 males) with a median age of 67 years were included in this study. Reticulation, GGO, honeycombing, and consolidation extents showed a positive correlation with KL-6 levels. [Reticulation, correlation coefficient (r) = 0.567, p < 0.001; GGO, r = 0.355, p < 0.001; honeycombing, r = 0.174, p = 0.046; and consolidation, r = 0.446, p < 0.001]. Additionally, the area under the ROC of the combined reticulation and KL-6 for hospitalizations due to respiratory reasons was 0.810 (p < 0.001)., Conclusions: Quantitative analysis of CT features and serum KL-6 levels ascertained a positive correlation between the two. In addition, the combination of reticulation and KL-6 shows potential for predicting hospitalizations of ILD patients due to respiratory causes. The combination of reticulation, focusing on phenotypic change in lung parenchyma, and KL-6, as an indicator of lung injury extent, could be helpful for monitoring and predicting the prognosis of various types of ILD., (© 2024. The Author(s).)

Rationale: Cough is a key symptom in patients with fibrotic interstitial lung disease (ILD). Objectives: This study evaluated the prevalence, longitudinal change, associations, and prognostic significance of cough severity in patients with fibrotic ILD. Methods: We included consecutive patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD who completed the 100-mm Cough Severity Visual Analog Scale from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. Baseline cough severity and associations with patient demographics and clinical factors were determined. Relationships between baseline cough severity and health outcomes were evaluated. Measurements and Main Results: Patients with IPF ( n  = 1,061) had higher median baseline cough severity than those with non-IPF fibrotic ILD ( n  = 2,825) (24 vs. 20 mm; P  < 0.001), with worse cough associated with gastroesophageal reflux disease for both cohorts. Worse cough severity was independently associated with worse health-related quality of life at baseline, larger annualized decline in Dl CO , development of disease progression, and reduced transplant-free survival in both IPF and non-IPF fibrotic ILD cohorts. The IPF cohort (2.2 mm; 95% confidence interval, 1.6-2.9 mm) had larger annualized increments in cough severity than the non-IPF fibrotic ILD cohort (1.1 mm; 95% confidence interval, 0.8-1.4 mm; P  = 0.004). There was no difference in worsening cough over time comparing those receiving and not receiving ILD-targeted therapy or with and without lung function decline. Conclusions: Cough is common in patients with IPF and non-IPF fibrotic ILD, with increasing cough severity over time irrespective of ILD-targeted therapy. Patient-reported cough severity has prognostic implications on health-related quality of life, disease progression, and survival in fibrotic ILD.

We evaluated the utility of transmission electron microscopy (TEM) in transbronchial lung cryobiopsy (TBLC) samples from 16 consecutive patients undergoing routine evaluation of fibrotic interstitial lung disease (ILD). Next to routine pathology examination, 1 to 2 TBLC samples were prepared for TEM analysis and evaluated using a Zeiss LEO EM 910. Subpleural cryobiopsies and unfrozen excision biopsies from fresh lobectomy tissue of non-ILD lung cancer patients served as controls. TEM provided high-quality images with only minor cryoartifacts as compared to controls. Furthermore, in several ILD patients we found marked microvascular endothelial abnormalities like luminal pseudopodia-like protrusions and inner surface defects. These were extensively present in four (25%), moderately present in seven (43.8%), and largely absent in five (31.3%) patients. A higher degree of TEM endothelial abnormalities was associated with younger age, non-specific interstitial pneumonia pattern, higher broncho-alveolar lavage lymphocyte count, positive autoantibodies, and lower spirometry, diffusion capacity and oxygenation biomarkers. We conclude that TEM evaluation of TBLC samples from ILD patients is feasible, while the observed microvascular alterations warrant further evaluation., (© 2024. The Author(s).)

Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis., Competing Interests: Conflict of interest: A. Arvanitaki, M.A. Gatzoulis and C. McCabe declare no conflicts of interest relevant to this work. ​G.P. Diller has received honoraria and travel grants from Janssen Global. L.C. Price has received consultancy fees from Janssen and educational support and conference support from Janssen and Ferrer. S.J. Wort has received consultancy fees from Janssen, Acceleron, MSD, Ferrer and Bayer, honoraria from Janssen, Acceleron, MSD, Ferrer and Bayer, as well as travel and research grants from Janssen and Ferrer., (Copyright ©The authors 2024.)

Background: Although the imaging manifestations of pulmonary sarcoidosis have been described in detail in previous studies, a consensus has not been reached on the imaging presentation of non-specific interstitial pneumonia (NSIP) lookalike pattern as a distinct pattern in the diagnosis of pulmonary sarcoidosis in high-resolution computed tomography (HRCT). No cases of pulmonary sarcoidosis comorbid with NSIP have been reported., Case Presentation: A 53-year-old male presented to the hospital with a five-year history of recurrent coughing up sputum and a four-year history of shortness of breath. In addition to the typical features of pulmonary sarcoidosis, the patient's HRCT also showed unexpected interstitial changes in the lower lobes of both lungs, suggesting an NSIP pattern. Histopathology of the lung tissue in this region confirmed well-formed noncaseating epithelioid granulomas and pathological modifications of NSIP. After a rigorous exclusion diagnosis combining the patient's clinical features, radiological and pathological findings, we diagnosed this patient with pulmonary sarcoidosis comorbid with NSIP., Conclusions: This suggests that NSIP may act as a rare comorbidity of pulmonary sarcoidosis thereby resulting in the patient's HRCT presenting differently from routine sarcoidosis imaging., (© 2024. The Author(s).)

To investigate the causal relationship between rheumatoid arthritis (RA) and interstitial lung disease (ILD) in the East Asian population, we utilized Mendelian randomization (MR). Publicly available summarized data from genome-wide association studies on RA (4199 cases and 208,254 controls), and the data on ILD (1046 cases and 176,974 controls) were obtained from BioBank Japan. Eligible single nucleotide polymorphisms from East Asian populations were obtained from genome-wide association studies as instrumental variables, and 11 RA-related single nucleotide polymorphisms (P < 5 × 10-8) were selected as instrumental variables. MR analysis was performed using inverse variance weighted, MR-Egger regression, weighted median, and MR-PRESSO with RA as the exposure data and ILD as the outcome data. Reliability was evaluated using Cochran Q test, MR-Egger intercept, leave-one-out analysis, and funnel plot. Inverse variance weighted results showed an odds ratio (95% confidence interval) of 1.29 (1.18-1.41), P = 3.99 × 10-8, indicating a positive association between RA and ILD. The reliability evaluation could adopt the fixed-effect model, and the absolute value of the MR-Egger regression intercept was 0.021, P > 0.05, and P value of Global Test in MR-PRESSO was 0.573. The test results of the leave-one-out showed that the results are robust, and the funnel plot indicated that the instrumental variables were not affected by potential factors. In conclusion, this study demonstrates that RA is a risk factor for ILD in the East Asian population., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Interstitial lung disease (ILD) may complicate the course of systemic autoimmune rheumatic disease (SARD) and diagnostic biomarkers are needed. Krebs von den Lungen-6 (KL-6), ferritin (FER) and interleukin 6 (IL-6) have been involved in the ILD development. Our study aimed to compare KL-6, FER, IL-6 and soluble mesothelin-related peptide (SMRP) concentrations in a cohort of idiopathic and SARD-ILD., Methods: 3169 patients were enrolled in the "UK Biomarkers in Interstitial Lung Disease (UK-BILD) Study". We selected patients affected by SARD-ILD and idiopathic ILD (usual interstitial pneumonia-idiopathic pulmonary fibrosis and fibrotic non-specific interstitial pneumonia). Serum marker concentrations were measured through chemiluminescent assays (Fujirebio Europe, Ghent, Belgium)., Results: 1013 patients were selected for the study: 520 (51.3%) had idiopathic ILD and 493 (48.7%) SARD-ILD. Idiopathic ILD patients displayed higher KL-6 values than SARD-ILD (p = 0.0002). FER and SMRP, though within normal ranges, were significantly higher in idiopathic ILD (p<0.0001). Logistic regression showed good sensitivity (69.4%) and specificity (80.4%) selecting the variables FER and KL-6 concentrations, age and gender-male correlated with a diagnosis of idiopathic ILD., Conclusion: Our study showed the excellent diagnostic value of KL-6 for detecting ILD, which irrespective of the final diagnosis and extent of disease, is always elevated and is a reliable biomarker of lung fibrosis in various diseases, ranging from idiopathic to autoimmune forms. Our study proposed an ILD differentiation model including clinical background. In this context, combination of serum markers and clinical data, as seen in our cohort, may lead to a further improvement in diagnostic accuracy for ILD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 d’Alessandro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Interstitial lung diseases (ILDs) are diverse pulmonary disorders marked by diffuse lung inflammation and fibrosis. The variability in characteristics and treatment approaches complicates diagnosis and management. In advanced cases requiring transplantation, determining indications and selecting suitable candidates presents additional challenges., Methods: Of all patients with non-IPF ILD between December 2016 to December 2022 were analyzed retrospectively. Patients were categorized into two groups: transplanted patients and deceased patients on the waiting list. Clinical data and survival outcomes were compared between groups., Results: Of the 43 patients, 20 underwent lung transplantation while 23 died awaiting transplantation. Waiting list mortality was 53.4%, with median waiting times similar between groups (3 months for transplant patients and 6 months for those on the waiting list). There were no significant differences between groups in age, gender, height, BMI, 6-minute walk test (6MWT), or forced vital capacity (FVC). The prevalence of pulmonary hypertension (PH) was 76.7% in right heart catheterizations, similar in both groups. One single and 19 bilateral lung transplants were performed. Overall, 13 of the 20 patients survived to discharge from the hospital. One-year mortality was 7/20 (35%). The median follow-up was 34 months, with a 1-year conditional survival of 90.9% at 3 years and 70.7% at 5 years., Conclusions: This study underscores the importance of further research into non-IPF ILDs. Lung transplantation remains a viable option that can significantly enhance both the quality and longevity of life for patients with advanced ILD., (© 2024. The Author(s).)

Interstitial lung disease (ILD) causes significant morbidity and mortality in patients with systemic autoimmune rheumatic diseases. Patients at high risk of ILD should be screened using high-resolution CT (HRCT), but there is no consensus as to which risk factors-or combination of risk factors-should prompt referral for HRCT. The course of autoimmune disease-associated ILD is highly variable, and it may not mirror the activity of the underlying autoimmune disease. Patients require close monitoring with periodic pulmonary function testing and symptom assessment and with repeat HRCT considered based on clinical assessment. The relevance of clinical and radiologic signs of progression-and their implications for management-ideally should be discussed by a multidisciplinary team. Management of autoimmune disease-associated ILD may involve immunosuppressant and/or antifibrotic therapy in addition to supportive care. It is important that treatment decisions be individualized to the needs and wishes of the patient. Regular follow-up is important to monitor disease progression and manage the adverse effects related to treatment.

Interstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high-resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non-fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non-IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group-wise analyses of metabolites altered in ILD phenotypes. We utilized limma one-way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p-values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl-hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non-ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Objective: Interstitial lung disease (ILD) resulting from connective tissue disease (CTD) greatly undermines people's health. Cyclophosphamide (CYC) is a widely used agent in treating CTD-ILD. We compared the efficacy and safety of oral and intravenous CYC in CTD-ILD treatment., Methods: The retrospectively enrolled CTD-ILD patients were divided into the oral and intravenous CYC groups. The chest high-resolution computed tomography examination, forced vital capacity (FVC), lung carbon monoxide diffusion capacity (Dlco) determinations, and 6 min walk test (6MWT) were performed pre-treatment and at the 3rd, 6th, and 12th months posttreatment. Radiographic ILD severity was assessed using the Warrick score. Krebs Von den Lungen-6, surfactant protein A (SP-A), SP-D, and erythrocyte sedimentation rate (ESR) before and at the 12th month post-treatment were determined. CYC cumulative dose and occurrence of adverse reactions during treatment were recorded., Results: CYC cumulative dose in the intravenous CYC group was reduced. Compared with oral CYC treatment, intravenous CYC caused decreased Warrick score and increased FVC and 6MWT at the 6th month, and elevated DLco at the 3rd and 6th months posttreatment. SP-A, SP-D and ESR levels in both groups were reduced 12 months posttreatment, with a more evident decrease in the intravenous CYC group. Intravenous CYC had lower total adverse reaction incidence., Conclusion: Compared with oral CYC, intravenous CYC decreases Warrick score and increases FVC and 6MWT at 6 months posttreatment, and reduces SP-A, SP-D, and ESR levels after 12 months of treatment, which shows low CYC cumulative dose and adverse reaction incidence in treating CTD-ILD., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Background: Interstitial lung diseases (ILD) is a group of lung disorders characterized by interstitial lung thickening due to inflammatory and fibrotic processes. Krebs von den Lungen-6 (KL-6) is a molecule secreted by damaged type II alveolar pneumocytes in the alveolar space. The goal of the present study was to compare two detection methods of KL-6 in both bronchoalveolar lavage (BAL) and serum from ILD patients at the moment of diagnosis., Methods: Patients with suspicious of ILD and followed at two Italian referral centres for rare lung diseases were included in the study. BAL fluid and serum were collected and analysed by chemiluminescent enzyme immunoassay (CLEIA) and fluorescent enzyme immunoassay (FEIA) methods provided by Tosoh Biosciences., Results: A total of 158 (mean age ± standard deviation, 61.5 ± 13.7, 65 females) patients were enrolled. A total of, 36 had diagnosis of idiopathic pulmonary fibrosis (IPF), 74 sarcoidosis, 15 connective tissue disease-ILD (CTD-ILD) and 33 other ILD. Diagnostic agreement between two methods was demonstrated for both BAL (r = 0.707, p < 0.0001) and serum (r = 0.816, p < 0.0001). BAL KL-6 values were lower than serum (p < 0.0001). IPF patients had higher serum KL-6 concentration than other ILDs (p = 0.0294), while BAL KL-6 values were lower in IPF than in non-IPF (p = 0.0023)., Conclusion: This study explored KL-6 concentrations through the CLEIA method in serum and BAL of patients with various ILDs, showing significant differences of biomarkers concentrations between IPF and other non-IPF ILDs. Our findings are promising as they provided further knowledge concerning KL-6 expression across different ILDs and may suggest its utility in differential diagnosis., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Objectives: Certain guidelines recommend caution when administering immunotherapy in patients with pre-existing interstitial lung disease (ILD) owing to the high incidence of pneumonitis induced by anti-cancer therapy. A prospective clinical trial assessing the safety of chemoimmunotherapy in patients with small-cell lung cancer (SCLC) and pre-existing ILD is warranted. Therefore, this study evaluated the safety and efficacy of chemoimmunotherapy in patients with extensive-stage (ES)-SCLC and mild idiopathic interstitial pneumonia (IIP)., Methods: In this multicenter prospective trial, patients with ES-SCLC and pre-existing mild chronic fibrosing IIP were recruited. Mild IIP was defined as the exclusion of poor pulmonary function, a definite usual interstitial pneumonia (UIP) pattern, and positivity for autoantibodies in blood tests. The patients received durvalumab, etoposide, and carboplatin every three weeks (induction phase), followed by 1,500 mg durvalumab every four weeks (maintenance phase). The primary endpoint was severe pneumonitis-free rate., Results: Twenty-one patients were included in the analysis. Among them, 13 patients displayed a probable UIP pattern, whereas eight patients exhibited an indeterminate for UIP pattern. Two patients (9.5 %) had pneumonitis of any grade during the induction phase; one had Grade 1 and the other had Grade 5 pneumonitis. No other patient developed pneumonitis during the maintenance phase. The severe pneumonitis-free rate was 95.2 % (95 % confidence interval (CI): 77.3-99.2 %). The median progression-free survival was 5.5 months (95 % CI: 3.6-6.4 months). Median overall survival was 10.7 months (95 % CI: 6.0 months to not reached)., Conclusions: Chemoimmunotherapy is a feasible treatment approach for patients with ES-SCLC and mild IIP., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Daichi Fujimoto reports financial support provided by AstraZeneca K.K. Ryota Shibaki received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Daichi Fujimoto received grants from AstraZeneca K.K. during the study and personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Janssen Pharmaceutical KK, Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Novartis Pharma KK outside of the submitted work. Eisaku Miyauchi received personal fees from AstraZeneca KK, Boehringer Ingelheim Japan Inc., Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck Biopharma Co. Ltd., Pfizer Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Amgen Inc., Thermo Fisher Scientific KK, Nippon Kayaku Co. Ltd., Sysmex Co. Ltd., KYORIN Pharmaceutical Co. Ltd., and Novartis Pharma KK outside the submitted work. Yoko Tsukita received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Daiichi Sankyo Co. Ltd., Eisai Co. Ltd., and Boehringer Ingelheim Japan Inc. outside the submitted work. Daisuke Arai has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Merck, and Nippon Kayaku Co. outside the submitted work. Yoshihiko Sakata received personal fees from AstraZeneca KK, Amgen, Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Takeda Pharmaceutical Co., Ltd., and Novartis Pharma KK outside the submitted work. Naoki Shingu received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Takeda Pharmaceutical Co. Ltd., and MSD KK outside the submitted work. Takashi Kijima received personal fees from Chugai Pharmaceutical Co. Ltd. outside the submitted work. Go Saito received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Pfizer, Daiichi Sankyo Company, and Novartis Pharma KK outside the submitted work. Yuki Sato received personal fees from AstraZeneca KK, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Eli Lilly Japan KK, Kyowa Kirin Co. Ltd., Daiichi Sankyo Co. Ltd., and Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Nippon Kayaku Co., Ltd., and Novartis Pharma KK outside the submitted work. Shinya Sakata received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd. outside the submitted work. Yoshihiko Taniguchi received personal fees from AstraZeneca KK, Bristol-Myers Squibb Co. Ltd., and Chugai Pharmaceutical Co. Ltd. outside the submitted work. Akito Hata has received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan KK, Pfizer Inc., and Boehringer Ingelheim outside the submitted work. Hirotaka Matsumoto received personal fees from AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD KK, Takeda Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Ono Pharmaceutical Co. Ltd., and Boehringer Ingelheim outside the submitted work. Nobuyuki Yamamoto has received personal fees from AstraZeneca KK, Chugai Pharmaceutical Co. Ltd., MSD KK, Ono Pharmaceutical Co. Ltd., Daiichi Sankyo, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Boehringer Ingelheim Japan Inc., Pfizer Inc., Amgen Inc., Janssen Pharmaceutical KK, Terumo, Eli Lilly Japan KK, Novartis Pharma KK, Merck Biopharma, Guardant Health Japan, Accuray Inc., AbbVie, Kyorin Pharmaceutical Co. Ltd., Tsumura & Co., and Miyarisan Pharmaceutical outside the submitted work. Other authors declare that they have no competing financial interests or personal relationships that could have influenced the work reported in this study.]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Interstitial lung disease (ILD) poses a serious threat in patients with rheumatoid arthritis (RA). However, the impact of cornerstone drugs, including methotrexate (MTX) and TNF inhibitor, on RA-associated ILD (RA-ILD) remains controversial., Methods: Using an SKG mouse model and single-cell transcriptomics, we investigated the effects of MTX and TNF blockade on ILD., Findings: Our study revealed that MTX exacerbates pulmonary inflammation by promoting immune cell infiltration, Th17 activation, and fibrosis. In contrast, TNF inhibitor ameliorates these features and inhibits ILD progression. Analysis of data from a human RA-ILD cohort revealed that patients with ILD progression had persistently higher systemic inflammation than those without progression, particularly among the subgroup undergoing MTX treatment., Interpretation: These findings highlight the need for personalized therapeutic approaches in RA-ILD, given the divergent outcomes of MTX and TNF inhibitor., Funding: This work was funded by GENINUS Inc., and the National Research Foundation of Korea, and Seoul National University Hospital., Competing Interests: Declaration of interests Dr. Sparks has received research support from Bristol Myers Squibb and Boehringer Ingelheim unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi, and UCB unrelated to this work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains challenging due to the scarcity of proven effective therapeutic options. This study aimed to investigate the effectiveness and safety of Janus kinase inhibitors (JAKi) in RA-ILD., Methods: We systematically reviewed the literature to identify studies evaluating the efficacy and safety of JAK inhibitors in RA-ILD. A meta-analysis was performed using the random-effects model., Results: The literature search identified seven observational studies assessing the safety and efficacy of JAKi in RA-ILD and three studies analyzing the risk of developing de novo ILD in RA patients treated with JAKi. Among 183 patients with RA-ILD, the pooled analysis demonstrated an increase of 2.07 % in %pFVC (95 % CI: 0.57-3.58; p = 0.007) and 3.12 % in %pDLCO (95 % CI: 2.11-4.12; p < 0.001). Thoracic HRCT scans showed improvement in 11 % of patients (95 % CI: 0.01-0.29). The pooled proportion of patients experiencing worsening of pre-existing ILD was 5 % (95 % CI: 0.01-0.11). Adverse events were reported in 14 % of cases (95 % CI: 0.08-0.21), with the frequency of clinically significant infections ranging from 4.5 % to 25 %. The risk of developing de novo ILD in patients receiving JAKi was low, with an incidence rate of 0.20 per 1000 person-years (95 % CI: 0.14-0.25). Comparisons with abatacept and rituximab suggested similar efficacy and safety profiles., Conclusion: JAKi are well tolerated and might be a viable treatment option for RA-ILD, offering comparable safety and efficacy to abatacept and rituximab., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests related to the preparation of this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Breathlessness frequently becomes severe among people with respiratory disease. Mirtazapine, a widely used antidepressant, has shown promise in the modulation of respiratory sensation and the response to it, as well as reducing feelings of panic, which often accompanies breathlessness. We aimed to determine the effectiveness of mirtazapine to alleviate severe persisting breathlessness., Methods: This international, multicentre, phase 3, parallel-group, double-blind, randomised, placebo-controlled trial across 16 centres in seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK), recruited adults with chronic obstructive pulmonary disease (COPD), interstitial lung diseases, or both, and grade 3 or 4 of the modified Medical Research Council breathlessness scale. Consenting participants were randomly assigned (1:1) to receive oral mirtazapine or matching placebo for 56 days. Randomisation was by minimisation. The initial mirtazapine dose was 15 mg, escalating to a maximum of 45 mg per day, tapered at treatment end. Participants, caregivers, assessors, and investigators were masked to group assignment. The primary outcome was worst breathlessness in the preceding 24 h measured on a 0-10 numerical rating scale (NRS), at 56 days post-treatment start, with follow-up to 180 days. The primary analysis was performed in the modified intention-to-treat population using multivariable multi-level repeated measures model. This trial was registered with ISRCTN (ISRCTN10487976 and ISRCTN15751764 [Australia and New Zealand]) and EudraCT (2019-002001-21) and is complete., Findings: Between Feb 4, 2021 and March 28, 2023, we enrolled 225 eligible participants (148 men and 77 women, 113 to the mirtazapine group and 112 to the placebo group). The median age was 74 years (IQR 67-78). No evidence of a difference was found in worst breathlessness at day 56 between mirtazapine and placebo (difference in adjusted mean NRS score was 0·105 [95% CI -0·407 to 0·618]; p=0·69). Although the study was underpowered, the primary endpoint effect did not reach the pre-specified treatment effect of 0·55 for worst breathlessness score reduction that the study was powered to detect for the primary analysis. There were 215 adverse reactions in 72 (64%) of 113 participants in the mirtazapine group versus 116 in 44 (40%) of 110 participants in the placebo group; 11 serious adverse events in six (5%) participants in the mirtazapine group versus eight in seven (6%) participants in the placebo group; and one (1%) suspected unexpected serious adverse reaction in the mirtazapine group. At day 56, there were three deaths in the mirtazapine group and two deaths in the placebo group. At day 180, there were seven deaths in the mirtazapine group and 11 deaths in the placebo group., Interpretation: Our findings suggested that mirtazapine of doses 15 to 45 mg daily over 56 days does not improve severe breathlessness among patients with COPD or interstitial lung diseases and might cause adverse reactions. Based on these findings, we do not recommend mirtazapine as a treatment to alleviate severe breathlessness., Funding: EU Horizon 2020 (grant agreement No. 825319); Cicely Saunders International Breathlessness Programme; National Institute for Health and Care Research Applied Research Collaboration South London; Australian National Health and Medical Research Council-EU (application ID: APP1170731)., Competing Interests: Declaration of interests IJH reports grants from EU, Marie Curie Cancer Care, and National Institute for Health and Care Research (NIHR), and is Scientific Director of Cicely Saunders International, NIHR Emeritus Senior Investigator, and is an Honorary Clinical Consultant in Palliative Medicine for hospitals under Kings College Hospital National Health Service Foundation Trust outside of the submitted work. CEB reports grants from the EU, NIHR, AstraZeneca as well as an industry collaboration and a personal fee from Roche outside of the submitted work. JMBr reports grants from the EU and reports being an uncompensated NIHR Health Technology Assessment Funding Committee Chair outside of the submitted work. DCC reports personal fees from Helsinn Pharmaceuticals, Mayne Pharma International, Nous Group, iCare Dust Disease Board, and an unpaid consultant to Chris O'Brien Lighthouse outside of the submitted work. BF reports grants from the Wellcome Trust and is a member of the Ethics Advisory Board Our Future Health, Assurance Board member Cass Review, EU appointed Ethics Advisor to the River EU project, Advisory Board Member Italian MS ConCure project, Advisory Group for Monash University, and Advisory Panel Member for Economic and Social Research Council outside of the submitted work. SPH reports personal fees from Trevi Therapeutics, Boehringer Ingelheim, Chiesi, and is a Trustee for Action for Pulmonary Fibrosis outside of the submitted work. CB, MJJ, AOO, KR, and STS report grants from the EU. MM reports grants from the EU, UKRI, and NIHR. MK and PJ report grants from the EU and Poland Ministry of Science and Higher Education for participation in Horizon 2020. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Patients with early-stage lung cancer and interstitial lung disease have a poorer prognosis than those without interstitial lung disease. This study aimed to compare the long-term outcomes of lobar and sublobar resections in these patients., Methods: We retrospectively analyzed 138 consecutive patients with clinical stage I non-small cell lung cancer and interstitial lung disease who underwent surgical treatment at two institutions between January 2010 and December 2020. Propensity score matching analysis was performed to adjust for baseline characteristics., Results: Thirty-six patients underwent sublobar resection and 102 underwent lobar resection. The median follow-up was 45.7 months. In all patients, 5-year overall survival (OS) rates were 33.2% and 73.2%, and 5-year recurrence-free survival (RFS) rates were 24.2% and 60.1% in the sublobar and lobar resection groups, respectively (p < 0.01, <0.01). Death due to lung cancer and locoregional recurrence were significantly more frequent in the sublobar resection group than in the lobar resection group (p = 0.034, <0.01, respectively). On propensity score matching analysis, the 5-year OS rates of the 19 matched pairs were 46.3% and 73.2%, and the RFS rates were 31.6% and 67.6% in the sublobar and lobar resection groups, respectively (p = 0.036, <0.01). The Cox proportional hazards model demonstrated a significant association between lobar resection and improved survival (p = 0.047)., Conclusion: The patients in the lobar resection group had better survival rates than those in the sublobar resection group. In terms of long-term prognosis, deliberately limited surgery may not be necessary for patients who tolerate lobectomy., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

As the clinical course of systemic sclerosis (SSc) varies widely, prognostic indicators have been sought to predict the outcomes of individual patients. Racial differences in SSc render it necessary to validate prognostic indicators in different patient cohorts. In this study, we aimed to assess clinical and laboratory parameters in Japanese patients with early-stage SSc with diffuse cutaneous involvement and/or interstitial lung disease, and identify predictive factors for disease progression. We performed multivariate analyses of baseline clinical information to estimate symptoms 4 years later in Japanese patients with diffuse cutaneous SSc and/or SSc with interstitial lung disease. Patients were enrolled in the study within 5 years of disease onset at 10 Japanese SSc centers. Over 12 years, 115 patients followed up for 4 years were included in this study. The modified Rodnan skin score (mRSS) at 4 years correlated with the baseline mRSS and finger-to-palm distance, defined as the average length from the distal tip of the fourth finger to the distal palmar crease. The percentage predicted vital capacity (%VC) in year 4 positively and negatively correlated with initial %VC and the presence of anti-topoisomerase I antibodies, respectively. The Health Assessment Questionnaire Disability Index (HAQ-DI) at 4 years was positively and negatively associated with baseline HAQ-DI and %VC, respectively. The occurrence of digital ulcers within 4 years was associated with the initial presence of digital ulcers, finger-to-palm distance, and the presence of digital pitting scars and anti-topoisomerase I antibodies. This study identified several factors that may predict the progression of early-stage SSc in Japanese patients. Finger-to-palm distance may be a useful tool for predicting the progression of skin thickening and the development of digital ulcers in the early stages of severe SSc, but larger, long-term prospective studies are needed to confirm our findings., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Objectives: We performed a systematic review and meta-analysis to assess whether patients with connective tissue disease (CTD)-associated interstitial lung diseases (ILD) have an increased prevalence of cardiovascular (CV) disease and to validate associated risk factors., Methods: The PRISMA guidelines and PICO model were followed. We searched PubMed, Embase, Cochrane Library databases, Scopus, and Directory of Open Access Journals from inception to April 2024., Results: Thirteen studies comprising of 12,520 patients were included. Patients with CTD-ILD had a significantly increased risk of CV disease than patients with CTD (relative risk [RR] = 1.65, 95 % confidence interval [CI]: 1.41, 1.93), which are related to the proportion of men (P = 0.001) and the proportion of smokers (P = 0.045). Subgroup analysis found that patients with CTD-ILD had a higher risk of heart failure (RR = 2.84, 95 % CI: 1.50, 5.39), arrhythmia (RR = 1.55, 95 % CI: 1.22, 1.97) than patients with CTD. Another subgroup analysis showed that RA-ILD and SSc-ILD were associated with an increased risk of CV disease, but not IIM-ILD and MCTD-ILD (RA-ILD: RR = 2.19, 95 % CI: 1.27, 3.80; SSc-ILD: RR = 1.53, 95 % CI: 1.29, 1.82). Besides, patients with CTD-ILD had a higher prevalence of pulmonary arterial hypertension (RR = 2.48, 95 % CI: 1.69, 3.63) than patients with CTD., Conclusions: Patients with CTD-ILD had a 1.65 times increased risk of CV than patients with CTD-non-ILD, with increased prevalence of heart failure and arrhythmia. The risk of CV disease in SSc-ILD and RA-ILD is increased and we should pay more attention to male smokers. In addition, compared with CTD patients, CTD-ILD patients had a higher risk of pulmonary arterial hypertension., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

An 84-year-old man with a history of progressive interstitial pneumonia presented to our department with lung cancer (cT2aN0M0-IB) in right S6. Moreover, computed tomography revealed progressive diffuse pulmonary ossification in the bilateral lower pulmonary lobes. S6 segmentectomy was performed via video-assisted thoracoscopic surgery. It was difficult to divide the intersegmental plane using a stapler because of severe fibrosis and pulmonary ossification with bone marrow formation. Pulmonary ossification may be an important finding for surgical planning because of severe fibrosis or inflammation associated with severe lung condition. We suggest that the surgical indications and approaches for such cases should be reconsidered because pulmonary ossification can be associated with severe lung conditions., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)